PD is a progressive neurodegenerative disease involving a variety of neuronal population. Other then symptomatic therapies, there are no ways to stop the progression of underlying neurodegeneration in PD. Currently, abnormalities in alpha-synuclein is considered as a critical pathogenic agent in PD and other related diseases classified as alpha-synucleinopathies. Thus, understanding how alpha-synuclein abnormalities occur and causes neurodegeneration in brain appears critical for development of disease modifying therapies for PD. It should noted that effective disease modifying therapies will allow for more effective palliative therapies and provide significant added clinical relief for PD patiens. In the last several years, we have been using cellular models and transgenic mouse models of alpha-synucleinoapthies to identify cell biology and pathogenic processes relevant to understanding alpha-synucleinopathy. This effort has lead to the finding that alpha- synuclein accumulates in Endoplasmic Reticulum (ER) and converts to toxic oligomers in ER. Accumulation of toxic alpha-synuclein oligomers are closely followed by onset of chronic ER stress response. The significance of ER stress to alpha-synucleinopathy is supported by the fact that pharmacological treatment with an anti-ER stress compound, Salubrinal, significantly delays disease onset in mutant alpha-synuclein Tg mouse model and attenuates neuropathology in an AAV-alpha-synuclein rat model of SNpc degeneration. These results suggest that ER stress response pathway, particularly accumulation of phospho-eIF2alpha targeted by Salubrinal, could be explored as therapeutic target for PD. However, complexities of alpha-synucleinopathy in vivo require that our hypothesis need validation at molecular levels. With these issues in mind, we will use series of mutant mouse models targeting the Perk/eIF2alpha arm of the ER stress response to establish importance of ER stress response in neurodegeneration associated models of alpha-synuclein toxicity and a chronic toxin model of dopaminergic neurodegeneration. In addition, we will also provide biochemical and cell biological characterization of the toxic alpha-synuclein oligomers accumulating in the ER. These studies will establish the value of ER stress pathway, particuarly Perk/eIF2 alpha components, as targets for development of novel therapies for PD.